Methods of administering CRF antagonists

ABSTRACT

Compounds of the formula ##STR1## wherein B, R 3 , R 4 , R 5  and R 6  are as defined herein with reference to formula IX have corticotropin-releasing factor antagonist activity and as such are of use in the treatment of panics, phobias and other stress-related disorders.

BACKGROUND OF THE INVENTION

The present invention relates to the treatment of certain illnesses byadministering novel corticortropin-releasing factor (CRF) antagonists.

CRF antagonists are mentioned in U.S. Pat. No. 4,605,642 and 5,063,245referring to peptides and pyrazolinones, respectively. The importance ofCRF antagonists is set out in the literature, e.g. as discussed in U.S.Pat. No. 5,063,245. A recent outline of the different activitiespossessed by CRF antagonists is found in M. J. Owens et al., Pharm.Rev., Vol. 43, pages 425 to 473 (1991 ).

The CRF antagonists administered according to the invention aredescribed in copending U.S. patent applications Ser. No. 08/448,534(filed Jun. 14, 1995), 08/448,529 (filed Jun. 14, 1994), 08/481,413(filed Jun. 15, 1995), and 08/448,539 (filed Jun. 14, 1995). (DocketNos. 8224A, 8225A, 8226A and 8308A, respectively), all of which areincorporated herein by reference.

SUMMARY OF THE INVENTION

The present invention relates to the treatment of certain illnesseswhich comprises administering to a subject in need of such treatment aneffective amount of a compound of the formula ##STR2## and thepharmaceutically acceptable acid addition salts thereof, wherein A isCH₂ ;

R₁, R₂ and R₃ are each independently linear C₁ -C₆ alkyl, branched C₃-C₈ alkyl, C₃ -C₈ alkenyl wherein the double bond is not adjacent to theN or X when X, is oxygen or sulfur, or C₃ -C₇ cycloalkyl (CH₂)_(n)wherein n is 0, 1, 2, 3 or 4; or R₁ and R₂ when taken together with thenitrogen form a saturated four, five or six membered ring optionallycondensed with benzo; and R₃ may also be (CH₂)_(q) Q₁ R₁₉ wherein q is0, 1 or 2, Q₁ is Q, S, NH, N(C₁ -C₆ alkyl) or a covalent bond when X isnot a covalent bond, and R₁₉ is hydrogen, linear C₁ -C₆ alkyl, branchedC₃ -C₈ alkyl, C₃ -C₈ alkenyl, C₃ -C₈ cycloalkyl or C₃ -C₆ cycloalkyl(CH₂)_(n) wherein n is 1 to 4;

X₁ is a covalent bond, CH₂, NR wherein R is hydrogen or linear C₁ -C₆alkyl, O, or S;

Y is phenyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl,pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl,benzothiazolyl, isothiazolyl, benzisothiazolyl, isoxazolyl,benzisoxazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl,oxazolyl, benzoxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, orpiperidinyl, each of which may be substituted by one to three of any oneof fluoro, chloro, bromo, or methyl, or one of trifluoromethyl; with theproviso that Y is not unsubstituted phenyl; and

Z is ##STR3## wherein the B ring is phenyl, naphthyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazilyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thienyl, or indolyl, each of which may besubstituted by methyl, methoxy, fluoro, chloro, bromo or iodo; or asaturated 5- or 6-membered carbocyclic ring or a partially unsaturatedring having one or two double bonds;

R₄, is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, or hydroxy, fluoro,chloro, bromo, iodo, or trifluoromethyl;

R₅ is hydrogen, linear C₁ -C₆ alkyl, branched C₃ C₈ alkyl, C₃ C₈alkenyl, or (CH₂)_(o) -X2-(CH₂)r-Q2-R6;

R₆ is hydrogen, linear C₁ -C₆ alkyl, branched C₃ -C₈ alkyl, or C₃ -C₈alkenyl;

X₂ and Q₂ are each independently O, S, NH, N(C₁ -C₆ alkyl), or one of X₂and Q may be a covalent bond;

m is 0 or 1;

o is 1 or 2;

p is 1 or 2;

r is 0, 1, or 2; ##STR4## wherein R₄ and R₅ are as defined above, and tand u are each independently 1 or 2;

(c) NR₇ R₈ wherein R₇ and R₈ are each independently hydrogen, C₁ -C₆linear alkyl, branched C₃ -C₈ alkyl, C₃ -C₈ alkenyl, (CH₂)_(v) CH₂ OH,(CH₂)_(v) --NR₉ R₁₀, wherein v is 0 to 3, and R₉ and R₁₀ are eachindependently hydrogen, or linear C₁ -C₆ alkyl; C₁ -C₁₂ cycloalkyl, (C₃-C₁₂ cycloalkyl) (CH₂)_(n), (C₆ -C₁₀ bicycloalkyl) (CH₂)_(n), wherein nis 0 to 4, benzofused C₃ -C₆ cycloalkyl, C₁ -C₆ hydroxyalkyl, phenyl,phenyl (C₁ -C₃ alkylene), each of which may be substituted by one or twoof hydroxy, fluoro, chloro, bromo, C₁ -C₅ alkyl, or C₁ -C₅ alkoxy; or R₇and R₈ may be taken together with the nitrogen to form a saturated orpartially unsaturated 5-to 7-membered ring which may contain one of O,S, NH or N(C₁ -C₆ alkyl) and which may be substituted by C₁ -C₆ alkyl,hydroxy or phenyl wherein any double bond(s) are not adjacent to anyheteroatoms; ##STR5## wherein B, R₄ and R₅ are as defined above, w, x, yand z are each independently 1 or 2, and W is (CH2)_(q) wherein q is asdefined above, N(C₁ -C₆ alkyl), or oxygen; ##STR6## wherein B, R₄, m andp are as defined above; ##STR7## wherein B and R₄ are as defined above;(g) O(CH₂)_(v) R₁₁

wherein v is 0 to 3 and R₁₁ is linear C₁ -C₆ alkyl, branched C₃ -C₈alkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, thienyl,benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl,benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl,isothiazolyl, benzisothiazolyl, isoxazolyl, benzisoxazolyl, triazolyl,pyrazolyl, pyrrolyl, indolyl, azaindolyl, oxazolyl, benzoxazolyl,pyrrolidinyl, thiazolidinyl, morpholinyl, piperidinyl, or thienyl, eachof which may be substituted by one or two of any one of fluoro, chloro,bromo, methyl, or trifluoromethyl; ##STR8## and the pharmaceuticallyacceptable acid addition salts thereof, wherein A is C═O or SO₂, or Aand R₁ together with the carbons to which they are attached formpyrimidinyl or 5-pyridyl which may be substituted by R₅ which ishydrogen, C₁ -C₆ alkyl, fluoro, chloro, bromo, hydroxy, amino, O(C₁ -C₆alkyl), NH(C₁ -C₆ alkyl), N(C₁ -C₆ alkyl)(C₁ -C6 alkyl), SH, S(O)_(n)(C₁ -C₆ alkyl) wherein n=0, 1 or 2, wherein said C₁ -C₆ alkyl may besubstituted by from 1 to 3 substituents R₆ which is hydroxy, amino, C₁-C₃ alkoxy, dimethylamino, diethylamino, methylamino, ethylamino,NH(C═O)CH₃, fluoro, chloro, bromo or C₁ -C₃ thioalkyl;

R₁ is hydrogen, C₁ -C₆ alkyl, amino, O(C₁ -C₆ alkyl), NH(C₁ -C₆ alkyl),N(C₁ -C₆ alkyl)(C₁ -C₆ alkyl), wherein said C₁ -C₆ alkyl may besubstituted by from 1 to 3 substituents R₆ as defined above;

R₂ is hydrogen, C₁ -C₆ alkyl, hydroxy, amino, O(C₁ -C₆ alkyl), NH(C₁ -C₆alkyl), N(C₁ -C₆ alkyl)(C₁ -C₆ alkyl), SH, S(O)_(n) (C₁ C₆ alkyl)wherein n=0, 1, or 2, cyano, hydroxy, carboxy, or amido, wherein saidalkyls may be substituted by one to three of hydroxy, amino, carboxy,amido, NH(C═O)(C₁ -C₆ alkyl), N(C₁ -C₆ alkyl)(C₁ -C₆ alkyl), (C═O)O(C₁-C₆ alkyl), C₁ -C₃ alkoxy, C₁ -C₃ thioalkyl, fluoro, bromo, chloro,iodo, cyano or nitro;

R₃ is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl,benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl,benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl,azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl,morpholinyl, pyridinyl, tetrazolyl, or 9 to 12 membered bicycloalkyl,optionally containing one to three of O, S or N--Z wherein Z ishydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkanoyl, phenyl or phenylmethyl, whereineach one of the above groups may be substituted independently by fromone to three of fluoro, chloro, bromo, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, ortrifluoromethyl, or one of cyano, nitro, amino, NH(C₁ -C₆ alkyl), N(C₁-C₄ alkyl)(C₁ -C₂ alkyl), COO(C₁ -C₄ alkyl), CO(C₁ -C₄ alkyl), SO₂ NH(C₁-C₄ alkyl), SO₂ N(C₁ -C₄ alkyl)(C₁ -C₂ alkyl), SO₂ NH₂, NH₂ SO₂ (C₁ -C₄alkyl), S(C₁ -C₆ alkyl), SO₂ (C₁ -C₆ alkyl), wherein said C₁ -C₄ alkyland C₁ -C₆ alkyl may be substituted by one or two of fluoro, chloro,hydroxy, amino, methylamino, dimethylamino or acetyl; and

R₄ is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl,benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl,benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl,azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl,morpholinyl, pyridinyl, tetrazolyl, or 3 to 8-membered cycloalkyl or 9to 12-membered bicycloalkyl, optionally containing one to three of O, Sor N--Z wherein Z is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkanoyl, phenyl orphenylmethyl, wherein each of the above groups may be substitutedindependently by from one to three of fluoro, chloro, bromo,trifluoromethyl, C₁ -C₆ alkyl or C₁ -C₆ alkoxy, or one of cyano, nitro,amino, NH(C₁ -C₆ alkyl), N(C₁ -C₄ alkyl)(C₁ -C₂ alkyl), COO(C₁ -C₄alkyl), CO(C₁ -C₄ alkyl), SO₂ NH(C₁ -C₄ alkyl), SO₂ N(C₁ -C₄ alkyl)(C₁-C₂ alkyl), SO₂ NH₂, NH₂ SO₂ (C₁ -C₄ alkyl), S(C₁ -C₆ alkyl), SO₂ (C₁-C₆ alkyl), wherein said C₁ -C₄ alkyl and C₁ -C₆ alkyl may besubstituted by one or two of fluoro, chloro, hydroxy, amino,methylamino, dimethylamino or acetyl; provided that (1) R₄ is notunsubstituted phenyl; (2) when R₁ is amino, R₂ is methylthio, R₄ is2,4,6-trichlorophenyl, and A is C═O, then R₃ is not 2-chlorophenyl; and(3) R₁ and R₂ are not both hydrogen; ##STR9## and the pharmaceuticallyacceptable acid addition salts thereof, wherein A is NR₁ R₂, CR₁ R₂ R,or C(═CR₁ R₁₂)R₂, NHCR₁ R₂ R₁₁, OCR₁ R₂ R₁₁, SCR₁ R₂ R₁₁, NHNR₁ R₂, CR₂R₁₁ NHR₁, CR₂ R₁₁, OR₁, CR₂ R₁₁ SR₁ or C(O)R₂ ;

R₁ is hydrogen, or C₁ -C₆ alkyl which may be substituted by one or twosubstituents R₆ independently selected from the group consisting ofhydroxy, fluoro, chloro, bromo, iodo, C₁ -C₆ alkoxy, ##STR10## (C₁ -C₂alkyl), amino, NH(C₁ -C₄ alkyl), N(C₁ -C₂ alkyl)(C₁ -C₄ alkyl), S(C₁ -C₆alkyl), OC(O)NH(C₁ -C₄ alkyl), N(C₁ -C₂ alkyl)C(O)(C₁ -C₄ alkyl),##STR11## (C₁ -C₂ alkyl), SH, CN, NO₂, SO(C₁ -C₄ alkyl), SO₂ (C₁ -C₄alkyl), SO₂ NH(C₁ -C₄ alkyl), SO₂ N(C_(C) ₄ alkyl)(C₁ -C₂ alkyl), andsaid C₁ -C₆ alkyl may contain one or two double or triple bonds;

R² is C₁ -C₁₂ alkyl, al or (C₁ -C₁₀ alkylene)aryl wherein said al isphenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl,pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,isothiazolyl, benzisothiolyl, thiazolyl, isoxazolyl, benzisoxazolyl,benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl,oxazolyl, or benzoxazolyl; 3- to 8-membered cycloalkyl or (C₁ -C₆alkylene) cycloalkyl, wherein said cycloalkyl may contain one or two ofO, S or N--Z wherein Z is hydrogen, C₁ -C₄ alkyl, benzyl or C₁ -C₄alkanoyl, wherein R² may be substituted independently by from one tothree of chloro, fluoro, or C₁ -C₆ alkyl, or one of hydroxy, bromo,iodo, C₁ -C₆ alkoxy, ##STR12## O--C--N(C₁ -C₄ alkyl)(C₁ -C₂ alkyl), S(C₁-C₆ alkyl), NH₂, NH(C₁ -C₂ alkyl), N(C₁ -C₂ alkyl) (C₁ -C₄ alkyl), N(C₁-C₄ alkyl)- ##STR13## SH, CN, NO₂, SO(C₁ -C₄ alkyl), SO₂ (C₁ -C₄ alkyl),SO₂ NH(C₁ -C₄ alkyl), SO₂ N(C₁ -C₆ alkyl)(C₁ -C₂ alkyl), and whereinsaid C₁ -C₁₂ alkyl or C₁ -C₁₀ alkylene may contain one to three doubleor triple bonds; or

NR₁ R₂ or CR₁ R₂ R₁₁ may form a 4- to 8-membered ring optionallycontaining one or two double bonds or one or two of O, S or N--Z whereinZ is hydrogen, C₁ -C₆ alkyl, benzyl, or C₁ -C₄ alkanoyl;

R₃ is hydrogen, C₁ -C₆ alkyl, fluoro, chloro, bromo, iodo, hydroxy,amino, O(C₁ -C₆ alkyl), NH(C₁ -C₆ alkyl), N(C₁ -C₆ alkyl)(C₁ -C₆ alkyl),SH, S(C₁ -C₆ alkyl), SO(C₁ -C₄ alkyl), or SO(C₁ -C₆ alkyl), wherein saidC₁ -C₆ alkyl and C₁ -C₆ alkyl may contain one or two double or triplebonds and may be substituted by from 1 to 3 substituents R₇independently selected from the group consisting of hydroxy, amino, C₁-C₃ alkoxy, dimethylamino, diethylamino, methylamino, ethylamino,##STR14## chloro or C₁ -C₃ thioalkyl; R₄ is hydrogen, C₁ -C₆ alkyl,fluoro, chloro, bromo, iodo, C₁ -C₆ alkoxy, amino, NH(C₁ -C₆ alkyl),N(C₁ -C₆ alkyl) (C₁ -C₂ alkyl), SO_(n) (C₁ -C₆ alkyl), wherein n is 0, 1or 2, cyano, hydroxy, carboxy, or amido, wherein said C₁ -C₆ alkyls maybe substituted by one to three of hydroxy, amino, carboxy, amido,##STR15## NH(C₁ -C₄ alkyl), N(C₁ -C₄ alkyl)(C₁ -C₂ alkyl), ##STR16## C₁-C₃ alkoxy, C₁ -C₃ thioalkyl, fluoro, bromo, chloro, iodo, cyano ornitro;

R₅ is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl,benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl,benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl,pyrrolopyridyl benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl,piperazinyl, piperidinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or9- to 12-membered bicycloalkyl, optionally containing one or two of O, Sor N--Z wherein Z is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkanoyl, phenyl orbenzyl, wherein each one of the above groups may be substitutedindependently by from one to three of fluoro, chloro, bromo, formyl, C₁-C₆ alkyl, C₁ -C₆ alkoxy or trifluoromethyl, or one of hydroxy, iodo,cyano, nitro, amino, cyclopropyl, NH(C₁ -C₄ alkyl), N(C₁ -C₄ alkyl)(C₁-C₂ alkyl), COO(C₁ -C₄ alkyl), CO(C₁ -C alkyl), SO₂ NH(C₁ -C₄ alkyl),SO₂ N(C₁ -C₄ alkyl)(C₁ -C₂), SO₂ NH₂, NHSO₂ (C₁ -C₄ alkyl), S(C₁ -C₆alkyl), SO₂ (C₁ -C₆ alkyl), wherein said C₁ -C₆ alkyl and C₁ -C₆ alkylmay have one double or triple bond and may be substituted by one or twoof fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl;with the proviso that R₅ is not unsubstituted phenyl;

R₁₁ is hydrogen, hydroxy, fluoro, chloro, COO(C₁ -C₂ alkyl), cyano, orCO(C₁ -C₂ alkyl); and

R₁₂ is hydrogen or C₁ -C₄ alkyl;

(a) A is not straight chain C₁ -C₁₂ alkyl;

(b) R₅ is not a sugar group;

(c) when R₃ and R₄ are hydrogen and R₅ is chlorophenyl, then A is notNH--CH(CH₃)--(CH₂)₃ --N(C₂ H₅)₂ ;

(d) when R₃ and R₄ are hydrogen and A is NR₁ R₂ wherein R₁ is C₃ -C₇cycloalkyl, and R₂ is C₂ -C₆ alkenyl, phenyl-(C₁ -C₆ alkylene) orhetero-(C₁ -C₆ alkylene) wherein the hetero radical is furyl, thienyl orpyridinyl, and wherein said phenyl may be substituted by fluoro, chloro,bromo or iodo, then R₅ is not tetrahydrofuranyl or tetrahydropyranyl;

(e) when R₃ is methoxy, methylthio, or methylsulfonyl, R₄ is hydrogen,and R₅ is tetrahydrofuranyl or tetrahydropyranyl, then A is not NH(C₁-C₁₂ alkyl), morpholinyl, hydrazino, or NHC₂ H₄ C₆ H₅ which may besubstituted by one methyl or two methoxy;

(f) when R₃ is hydrogen, C₁ -C₆ alkyl, hydrazino, chloro, bromo, SH, orS (C₁ -C₄ alkyl), R₄ is hydrogen and R₅ is C₃ -C₈ cycloalkyl, then A isnot hydrazino, NH(C₁ -C₂ alkyl) or N(C₁ -C₆ alkyl) (C₁ -C₁₂ alkyl);

(g) when R₃ and R₄ are hydrogen and A is NH(CH₂)_(m) COOH wherein m is1-12, then R₅ is not phenyl substituted by one of fluoro, chloro, bromoor iodo;

(h) when R₃ is hydrogen, hydroxy, methylthio, chloro or NHbenzyl, R₄ ishydrogen, and R₅ is chlorophenyl or bromophenyl, then A is not NH(C₁-C₁₂ alkyl), NHallyl, or N(C₁ -C₆ alkyl) (C₁ -C₁₂ alkyl), wherein saidC₁ -C₁₂ alkyl may be substituted by NC₂ H₅, or NH benzyl which may besubstituted by one or two bromo, chloro, fluoro, NC₂ H₅ phenyl ormorpholinopropyl;

(i) when R₃ and R₄ are hydrogen and R₅ is nitrophenyl, then A is notNHR₂ wherein R₂ is C₁ -C₁₂ alkyl which may be substituted by twohydroxy, or R₂ is phenyl or benzyl;

(j) when R₃ is chloro or O(C₁ -C₆ alkyl), R₄ is hydrogen, and A is NR₁R₂ wherein R₁ and R₂ are independently hydrogen or C₁ -C₆ alkyl, then R₅is not chlorophenyl; and

(k) when R₃ is hydrogen, A is benzyl or phenethyl, and R₄ is fluoro,chloro, bromo or iodo, then R₅ is not 5'-deoxy-ribofuranosyl or5'-amino-5'-deoxy-ribofuranosyl; or ##STR17## and the pharmaceuticallyacceptable acid addition salts thereof, wherein B is NR₁ R₂, CR₁ R₂ R₁₁,C(═CR₂ R₁₂)R₁ , NHCR₁ R₂ R₁₁, OCR₁ R₂ R₁₁, SCR₁ R₂ R₁₁, NHNR₁ R₂, CR₂R₁₁ NHR₁, CR₂ R₁₁ OR₁, CR₂ R₁₁ SR₁, or C(O)R₂ ;

R₁ is hydrogen, or C₁ -C₆ alkyl which may be substituted by one or twosubstituents R₇ independently selected from the group consisting ofhydroxy, fluoro, chloro, bromo, iodo, C₁ -C₈ alkoxy, ##STR18## (C₁ -C₂alkyl), amino, NH(C₁ -C₄ alkyl), N(C₁ -C₂ alkyl)(C₁ -C₆ alkyl), S(C₁ -C₆alkyl), ##STR19## (C₁ -C₄ alkyl), SH, CN, NO₂, SO(C₁ -C₄ alkyl), SO₂ (C₁-C₄ alkyl), SO₂ NH(C₁ -C₄ alkyl), SO₂ N(C₁ -C₄ alkyl)(C₁ -C₂ alkyl), andsaid C₁ -C₆ alkyl may contain one or two double or triple bonds;

R₂ C₁ -C₁₂ alkyl, aryl or (C₁ -C₁₀ alkylene)aryl wherein said aryl isphenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl,pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,isothiazolyl, benzisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl,benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl,oxazolyl, or benzoxazolyl; 3- to 8-membered cycloalkyl or (C₁ -C₆alkylene) cycloalkyl, wherein said cycloalkyl may contain one or two ofO, S or N--Z wherein Z is hydrogen, C₁ -C₄ alkyl, benzyl or C₁ -C₄alkanoyl, wherein R₂ may be substituted independently by from one tothree of chloro, fluoro, or C₁ -C₄ alkyl, or one of hydroxy, bromo,iodo, C₁ -C₆ alkoxy, ##STR20## (C₁ -C₂ alkyl), S(C₁ -C₆ alkyl), NH₂,NH(C₁ -C₂ alkyl), N(C₁ -C₂ alkyl) (C₁ -C₄ alkyl), ##STR21## (C₁ -C₄alkyl), SH, CN, NO₂, SO(C₁ -C₄ alkyl), SO₂ (C₁ -C₄ alkyl), SO₀₂ NH(C₁-C₄ alkyl), SO₀₂ N(C₁ -C ₄ alkyl)(C₁ -C₂ alkyl), and wherein said C₁-C₁₂ alkyl or C₁ -C₁₀ alkylene may contain one to three double or triplebonds; or

NR₁ R₂ or CR₁ R₂ R₁₁, may form a saturated 3-to 8-membered ring of whichthe 5- to 8-membered ring may contain one or two double bonds or one ortwo of O, S or N--Z wherein Z is hydrogen, C₁ -C₄ alkyl, benzyl or C₁ -C₄ alkanoyl;

R₃ is hydrogen, C₁ -C₆ alkyl, fluoro, chloro, bromo, iodo, hydroxy,amino, O(C₁ -C₆ alkyl), NH(C₁ -C₆ alkyl), N(C₁ -C₄ alkyl)(C₁ -C₂ alkyl),SH, S(C₁ -C₄ alkyl), SO(C₁ -C₄ alkyl), or SO₂ (C₁ -C₄ alkyl), whereinsaid C₁ -C₄ alkyl and C₁ -C₆ alkyl may contain one double or triple bondand may be substituted by from 1 to 3 substituents R₈ independentlyselected from the group consisting of hydroxy, C₁ -C₃ alkoxy, fluoro,chloro or C₁ -C₃ thioalkyl;

R₄ is hydrogen, C₁ -C₆ alkyl, fluoro, chloro, bromo, iodo, C₁ -C₆alkoxy, amino, NH(C₁ -C₆ alkyl), N(C₁ -C₆ alkyl)(C₁ -C₂ alkyl), SO_(n)(C₁ -C₆ alkyl), wherein n is 0, 1 or 2, cyano, hydroxy, carboxy, oramido, wherein said C₁ -C₆ alkyls may be substituted by one hydroxy,trifluoromethyl, amino, carboxy, amido, ##STR22## NH(C₁ -C₄ alkyl), N(C₁-C₄ alkyl)(C₁ -C₂ alkyl), ##STR23## C₁ -C₃ alkoxy, C₁ -C₃ thioalkyl,fluoro, bromo, chloro, iodo, cyano or nitro;

R₅ is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,isothiazolyl, benzisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl,benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl,benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl,piperidinyl, piperazinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or9- to 12-membered bicycloalkyl, optionally containing one or two of O, Sor N--Z wherein Z is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkanoyl, phenyl orphenylmethyl, wherein each one of the above groups may be substitutedindependently by from one to three of fluoro, chloro, bromo, formyl, C₁-C₆ alkyl, C₁ -C₆ alkoxy or trifluoromethyl, or one of hydroxy, iodo,cyano, nitro, amino, NH(C₁ -C₆ alkyl), N(C₁ -C₄)(C₁ -C₂ alkyl), COO(C₁-C₆ alkyl), CO(C₁ -C₄ alkyl), SO₂ NH(C₁ -C₄ alkyl), SO₂ N((C₁ -C₄alkyl)(C₁ -C₄ alkyl), SO₂ NH₂ (C₁ -C₄ alkyl), NHSO₂ (C₁ -C ₄ alkyl),S(C₁ -C₆ alkyl), SO₂ (C₁ -C₆ alkyl), wherein said C₁ -C₄ alkyl and C₁-C₆ alkyl may be substituted by one or two of fluoro, chloro, hydroxy,C₁ -C₄ alkoxy, amino, methylamino, dimethylamino or acetyl wherein saidC₁ -C₄ alkyl and C₁ -C₆ alkyl may contain one double or triple bond;with the proviso that R_(s) is not unsubstituted phenyl;

R₆ is hydrogen, C₁ -C₆ alkyl, fluoro, chloro, bromo, iodo, C₁ -C₆alkoxy, formyl, amino, NH(C₁ -C₆ alkyl), N(C₁ -C₆ alkyl)(C₁ -C₂ alkyl),SO_(n) (C₁ -C₆ alkyl), wherein n is 0, 1 or 2, cyano, carboxy, or amido,wherein said C₁ -C₆ alkyls may be substituted by one hydroxy,trifluoromethyl, amino, carboxy, amido, ##STR24## NH(C₁ -C₄ alkyl), N(C₁-C₆ alkyl)(C₁ -C₂ alkyl), ##STR25## C₁ -C₃ alkoxy, C₁ -C₃ thioalkyl,fluoro, bromo, chloro, iodo, cyano or nitro;

R₁₁ is hydrogen, hydroxy, fluoro, chloro, COO(C₁ -C₂ alkyl), cyano, orCO(C₁ -C₂ alkyl); and

R₁₂ is hydrogen or C₁ -C₄ alkyl; with the proviso that (1) B is notstraight chain C₁ -C₁₂ alkyl, (2) when R₅ is unsubstituted cycloalkyl,R₃ and R₄, are hydrogen, and R₆ is hydrogen or methyl, then B is notNHR₂ wherein R₂ is benzyl or thienylmethyl, and (3) when R₅ isp-bromophenyl, and R₃, R₄ and R₆ are methyl, then B not methylamino orhydroxyethylamino, said disorders being selected from group consistingof panic, phobias including agoraphobia, social phobia, and simplephobia, obsessive-compulsive disorder, post-traumatic stress disorder,single episode depression, recurrent depression, dysthymia, bipolardisorders, cyclothymia, mood disorders, postpartum depression, childabuse induced depression, sleep disorders, stress induced painperception including fibromyalgia, fibromyalgic sleep disorders,rheumatoid arthritis, osteroarthritis, psoriasis, euthyroid sicksyndrome, syndrome of inappropriate antidiarrhetic syndrome hormone(ADH), bulimia nervosa eating disorder, and obesity.

More specific compounds of formula I of the invention include thosewherein Y is phenyl substituted by three substituents one each atpositions 2, 4 and 6, e.g. 2,4,6-trichlorophenyl,2,6-dichloro-4-trifluoromethylphenyl, or 2,6-dichloro-4-fluorophenyl.Other more specific compounds of formula I include those wherein XR₃ isethyl or methylthio, those wherein R₁ and R₂ are each methyl, and thosewherein Z is NR₇ R₈ and R₇ is phenyl or phenyl substituted by one offluoro, chloro, nitro, methyl or methoxy and R₈ is as defined above,preferably, (CH₂)₃ OH, CH₂ CH₂ OH or methyl.

Preferred compounds of formula I are those wherein Z is1,2,3,4-tetrahydroisoquinolin-2-yl substituted by R₅ which is--(CH₂)_(o) --X₂ --(CH₂)_(r) --Q₂ --R₆, more specifically R_(s) is--(CH₂)_(k) OH wherein k is an integer of 1 to 4, or --CH₂₀ CH₂ CH₂₀ R₆.Other preferred compounds of formula I are those wherein Z is1,2,3,4-tetrahydroquinolin-2-yl wherein R₅ is substituted at position 3,and the absolute configuration at the 3 position is either S or R orR,S.

Preferred compounds of the formula I include those wherein Z is asdefined in above subparagraph (h); and those wherein Z is as defined in(h), A is linked to position 1, F, G, H, I, J and K are each carbon, andR₁₄ is methoxy, ethoxy, isopropoxy, or cyclopropylmethoxy at position 2.

Other preferred compounds of formula I are those wherein Z is as definedin above subparagraph (h), A is linked to position 1, K is nitrogen, F,G, H, I, and J are each carbon, and R₁₄ is --X₂ --(CH₂)_(r) Q₂ R₆ atposition 2; those wherein Z is as defined in (h), A is linked toposition 1, K is nitrogen, F, G, H, I, and J are each carbon, and R₁₄ ismethoxy, ethoxy, isopropoxy, or cyclopropylmethoxy at position 2; andthose wherein Z is as defined in (h), A is at position 1, and R₁₄ isethoxy, isopropoxy or cyclopropylmethoxy at position 2. In thesepreferred compounds of formula I wherein Z is as defined in (h), R₁₂ andR₁₃ are preferably hydrogen.

Other preferred compounds of formula I are those wherein Z is as definedin subparagraph (a), B is phenyl, p and m are each 1, and R₅ is CH₂OCH₃.

Preferred compounds of formula I include those wherein Z is ##STR26##wherein B is phenyl, m is 0, and p is 1.

More specific compounds of the formula VII include those wherein R₃ isphenyl substituted independently with one or two of fluoro, chloro,bromo, methyl, trifluoromethyl, nitro, C₁ -C₆ alkyl, C₁ -C₆ alkyloxy,SO₂ NH₂, SO₂ NH(C₁ -C₆ alkyl), SO₂ N(C₁ -C₆ alkyl)₂, or R₃ is primary,secondary or tertiary alkyl of from 4-9 carbon atoms wherein said C₄ -C₉alkyl may contain from one to two double or triple bonds and may besubstituted by from 1 to 3 substituents R₆ which is hydroxy, amino, C₁-C₃ alkoxy, dimethylamino, diethylamino, methylamino, ethylamino,NH(C═O)CH₃, fluoro, chloro, bromo, or C₁ -C₃ thioalkyl,

More specific compounds of the formula VII are those wherein A is C═O,those wherein R₁ is amino, methylamino or dimethylamino; those whereinR₂ is ethyl or methylthio and those wherein R₄ is 2,4,6-trichlorophenyl,2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromethylphenyl or4-bromo-2,6-dimethylphenyl.

More specific compounds of formula VII further include those wherein R₃is phenyl which may be substituted at positions 2 or 5 with one or twoof methyl, C₂ -C₆ straight-chain or branched alkyl, trifluoromethyl,fluoro, chloro, bromo or nitro, those wherein A and R₁ together form apyrimidine ring, such that the bicyclic structure formed ispyrazolo[3,4-d]pyrimidine, and R₅ is substituted at the 6 position; andthose wherein R₄ is phenyl substituted independently with one or two offluoro, chloro, bromo, methyl, trifluoromethyl, nitro, C₁ -C₆ alkyl, C₁-C₆ alkyloxy, SO₂ NH₂, SO₂ NH(C₁ -C₆ alkyl), or SO₂ N(C₁ -C₆ alkyl)₂, R₄is 2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl,2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6-dimethylphenyl, andR₂ is methylthio, methyl or ethyl,

More specific compounds of formula VII also include those wherein R₃ isphenyl substituted independently with one or two of fluoro, chloro,bromo, methyl, trifluoromethyl, nitro, C₁ -C₆ alkyl, C₁ -C₆ alkyloxy,SO₂ NH₂, SO₂ NH(C₁ -C₆ alkyl), SO₂ N(C₁ -C₆ alkyl)₂, or R₃ is primary,secondary or tertiary alkyl of from 4-9 carbon atoms wherein said C₄ -C₉alkyl may contain from one to two double or triple bonds and may besubstituted by from 1 to 3 substituents R₆ which is hydroxy, amino, C₁-C₃ alkoxy, dimethylamino, diethylamino, methylamino, ethylamino,NH(C═O)CH₃, fluoro, chloro, bromo or C₁ -C₃ thioalkyl; R₄ is2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl,2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6-dimethylphenyl; R₁is amino, methylamino or dimethylamino; and R₂ is methylthio or ethyl.

More specific compounds of the formula VIII are those wherein A is NR₁R₁, NHCHR₁ R₂, or OCHR₁ R₂, wherein R₁ is C₁ -C₆ of hydroxy, fluoro orC₁ -C₂ alkoxy, and may contain one double or triple bond, and R₂ isbenzyl or C₁ -C₅ alkyl which may contain one double or triple bond,wherein said C₁ -C₆ alkyl or the phenyl in said benzyl may besubstituted by fluoro, C₁ -C₆ alkyl, or C₁ -C₆ alkoxy; and those whereinA is CR₁ R₂ R₁₁ wherein R₁ is C₁ -C₆ alkyl which may be substituted byone C₁ -C₆ alkoxy or hydroxy, R₂ is benzyl or C₁ -C₆ alkyl wherein saidC₁ -C₆ alkyl or the phenyl in said benzyl may be substituted by one C₁-C₆ alkyl, C₁ -C₆ alkoxy, fluoro, chloro or bromo, and R₁₁ is hydrogenor fluoro.

More specific compounds of the formula VIII include those wherein R₂ is(C₁ -C₄ alkylene)aryl wherein said aryl is phenyl, thienyl,benzofuranyl, furanyl, benzothienyl, thiazolyl, pyridyl orbenzothiazolyl.

More specific compounds of the formula VIII further include thosewherein R₂ is benzyl para-substituted by one of ethyl, t-butyl, methoxy,trifluoromethyl, nitro, fluoro chloro, or methyl.

Other more specific compounds of the formula VIII include those whereinR₂ is attached through a methylene or ethylene bridge to quinolyl,pyrrolyl, pyrrolidinyl, pyridyl, tetrahydropyranyl, cyclopropyl,piperidinyl, or benzyl-piperidinyl.

More specific compounds VIII further include those wherein R₁ or R₂ isC₁ -C₆ alkyl which may be substituted by one of hydroxy, methoxy,ethoxy, chloro, fluoro, OC(O)CH₃, OC(O)NHCH₃, or C(O)NH₂.

Other more specific compounds VIII include those wherein R₂ is C₁ -C₆alkyl substituted by two of methoxy or ethoxy, or one of COOC₂ H₅,methylthio, or phenyl.

Other more specific compounds VIII include those wherein A is NR₁ R₂ orCHR₁ R₂ in which R₁ and R₂ are taken together with N or CH to form a 5-or 6-membered ring having one more nitrogen, sulfur, and/or one oxygen,e.g. pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,isoxazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrazinyl or pyrimidyl.

Other more specific compounds VIII includes those wherein A is NHCHR₁ R₂or OCHR₁ R₂ in which CHR₁ R₂ is a 5- or 6-membered ring which maycontain one oxygen or sulfur, e.g. tetrahydrofuranyl,tetrahydrothiafuranyl and cyclopentanyl.

Preferred compounds of the formula IX of the invention are those whereinB is NR₁ R₂, NHCHR₁ R₂, or OCHR₁ R₂, wherein R₁ is C₁ -C₆ alkyl, whichmay be substituted by one of hydroxy, fluoro or C₁ -C₂ alkoxy, and maycontain one double or triple bond; those wherein R₂ is benzyl or C₁ -C₆alkyl which may contain one double or triple bond, wherein said C₁ -C₆alkyl or the phenyl in said benzyl may be substituted by fluoro, C₁ -C₆alkyl, or C₁ -C₆ alkoxy; those wherein R₃ is methyl, ethyl, fluoro,chloro or methoxy; those wherein R₄ and R₆ are independently hydrogen,methyl, or ethyl; and those wherein R₂ is phenyl substituted by two orthree substituents, said substituent being independently fluoro, chloro,bromo, iodo, C₁ -C, alkoxy, trifluoromethyl, C₁ -C₆ alkyl which may besubstituted by one of hydroxy, C₁ -C₄ alkoxy or fluoro and may have onedouble or triple bond, --(C₁ -C₄ alkylene)O(C₁ -C₂ alkyl), C₁ -C₃hydroxyalkyl, hydroxy, formyl, COO(C₁ -C₂ alkyl), --(C₁ -C₂alkylene)amino, or --C(O)(C₁ -C₄ alkyl).

In specific methods of the invention, said compound is

2-{1-[1-(2,6-dichloro-4-trifluoromethylphenyl)-5-dimethylamino-3-ethyl-1H-pyrazol-4-ylmethyl]-napthalen-2-yloxy}-ethanol;

enantiomeric[4-(3-methoxymethyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-5-methylsulfanyl-2-(2,4,6-trichlorophenyl)-2H-pyrazol-3-yl]-dimethylaminederived from(+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline;

enantiomeric[2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(3-ethoxymethyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-5-ethyl-2H-pyrazol-3-yl]-dimethylaminederived from (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline;

[2-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethyl-4(7-methoxyquinolin-8-ylmethyl)-2H-pyrazol-3-yl]-dimethylamine;

[2-(2,6-dichloro-4-trifluoromethylphenyl)-4-)2-ethoxy-napthalen-1-ylmethyl)-5-ethyl-2H-pyrazol-3-yl]-dimethylamine;

[4-(2-ethoxynapthalen-1-ylmethyl)-5-ethyl-2-(2,4,6-trichlorophenyl)-2H-pyrazol-3-yl]-dimethylamine;

[4-(7-methoxyquinolin-8-ylmethyl)-5-methylsulfanyl-2-(2,4,6-trichlorophenyl)-2H-pyrazol-3-yl]-dimethylamine;

2-{1 -[5-dimethlamino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazol-4-ylmethyl]-napthalen-2-yloxy}-ethanol;

enantiomeric[2-(2,6-dichloro-4-trifluoromethlphenyl)-5-ethyl-4-(3-methoxymethyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2H-pyrazol-3-yl]-dimethylaminederived from (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline;

[4-(2-cyclopropylmethoxynapthalen-1-ylmethyl)-5-methylsulfanyl-2-(2,4,6-trichlorophenyl)-2H-pyrazol-3-yl]-dimethylamine,

[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-dimethylphenyl)methanone,

[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-bis-trifluoromethylphenyl)methanone,

[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(5-isopropyl-2-methylphenyl)methanone,

[5-amino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazol-4-yl]-(5-isopropyl-2-methylphenyl)methanone,or

[5-amino-1-(4-bromo-2,6-dimethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-dibromophenyl)methanone,

[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-dimethylphenyl)methanone,

[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-bis-trifluoromethylphenyl)methanone,

[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(5-isopropyl-2-methylphenyl)methanone,

[5-amino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazol-4-yl]-(5-isopropyl-2-methylphenyl)methanone,or

[5-amino-1-(4-bromo-2,6-dimethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-dibromophenyl)methanone;

3-{(4-methyl-benzyl)-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-propan-1 -ol;

diethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl]-amine;

2-{butyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-ethanol;

dibutyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl}-amine;

butyl-ethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl]-amine;

butyl-ethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

butyl-cyclopropylmethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

di-1 -propyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl]-amine;

diallyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl]-amine;

butyl-ethyl-[6-chloro-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

butyl-ethyl-[6-methoxy-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl]-amine;

propyl-ethyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

4-(1-ethyl-propyl)-6-methyl-3-methylsulfanyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo [3,4-d]pyrimidine.

n-butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;

di-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;

ethyl-n-propyl-[2,5-dimethyl-7-2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;

diethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;

n-butyl-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;

2-{N-n-butyl-N-[2,5-dimethyl-7-2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-ethanol;

4-(1 -ethyl-propyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;

n-butyl-ethyl-[2,5-dimethyl-7-(2,4-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;

2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidyl-4-yl]-(1-ethyl-propyl)amine;or

2-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol.

DETAILED DESCRIPTION OF THE INVENTION

Whenever reference herein is made to groups (CH₂)_(q) Q₁ R₁₉ and(CH₂)_(o) --X₂ --CH₂)_(r) --Q₂ --R₆, then X₁ and Q₁, and X₂ and Q₂,respectively, are not both a heteroatom when q or r, respectively, is 1.

Whenever one of the substituents, e.g. Y or R₁ in formula I, is aheterocyclic group, the attachment of the group is through a carbonatom.

Whenever reference is made herein to alkyl, a straight and branchedchain alkyl of one to six carbon atoms is included, such as methyl,ethyl, isopropyl or hexyl.

Whenever reference is made herein to C₁ -C₆ alkyl, in the definition ofR₅ and R₁ formula VII, this includes unsaturated C₂ -C₆ alkyl, such asC₂ -C₅ alkyl having one double or triple bond, C₃ -C₆ alkyl having twodouble bonds, and C₄ -C₆ alkyl having two triple bonds.

Whenever reference is made herein to 3- to 8-membered cycloalkyl or 9-to 12-membered bicycloalkyl containing one to three of O, S or N--Z, itis understood that the oxygen and sulfur ring atoms are not adjacent toeach other. The three membered cycloalkyl has just one O, S or N--Z. Anexample of a six membered cycloalkyl having O and N is morpholinyl.

Whenever reference is made herein to C₁ -C₄ alkyl or C₁ -C₆ alkyl which"may contain one or two double or triple bonds" in the definitions ofR₁, R₂ and R₃, it is understood that at least two carbons are present inthe alkyl for one double or triple bond, and at least four carbons fortwo double and triple bonds.

Whenever an alkoxy group, e.g. in the definitions of R₁ and R₂ informula VIII, may have a double or triple bond, it is understood thatsuch double or triple bond is not directly attached to the oxygen.

The compounds of formulae I, VII, VIII and IX, their pharmaceuticallyacceptable salts, and their preparation are described in, respectively,U.S. patent applications Ser. No. 08/448,534, 08/448,529, 08/481,413,and 08/448,539. The compounds of formulae I, VII, VIII and IX, and theirpharmaceutically acceptable salts are designated hereafter as "theactive compound". It is noted that the active compounds are describedabove substantially in accordance with the respective patentapplications.

The acid addition salts are prepared in a conventional manner bytreating a solution or suspension of the free base of the activecompound with one chemical equivalent of a pharmaceutically acceptableacid. Conventional concentration or crystallization techniques areemployed in isolating the salts. Illustrative of suitable acids areacetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic,benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric,hydrobromic, hydroiodic, sulfamic, sulfonic acids such asmethanesulfonic, benzene sulfonic, p-toluenesulfonic, and related acids.

The active compounds may be administered alone or in combination withpharmaceutically acceptable carriers, in either single or multipledoses. Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solution and various organic solvents. Thepharmaceutical compositions formed by combining the active compounds andthe pharmaceutically acceptable carriers are then readily administeredin a variety of dosage forms such as tablets, powders, lozenges, syrups,injectable solutions and the like. These pharmaceutical compositionscan, if desired, contain additional ingredients such as flavorings,binders, excipients and the like. Thus, for purposes of oraladministration, tablets containing various excipients such as sodiumcitrate, calcium carbonate and calcium phosphate may be employed alongwith various disintegrants such as starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard filledgelatin capsules. Preferred materials for this include lactose or milksugar and high molecular weight polyethylene glycols. When aqueoussuspensions or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if desired,emulsifying or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin and combinations thereof.

For parenteral administration, solutions of the active compound insesame or peanut oil, aqueous propylene glycol, or in sterile aqueoussolution may be employed. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. These particular aqueous solutionsare especially suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

The effective dosage for the active compound depends on the intendedroute of administration and other factors such as age and weight of thepatient, as generally known to a physician. The dosage also depends onthe illness to be treated. The daily dosage will generally range fromabout 0.1 to 50 mg/kg of the body weight of the patient to be treated.The daily dosage may be given in a single dose or up to three divideddoses.

The methods for testing the active compounds for their CRF antagonistactivity are as described in Endocrinology, 116, 1653-1659 (1985) andPeptides 10, 179-188 (1989) which determine the binding affinity of atest compound for a CRF receptor. The binding affinities for the activecompounds, expressed as IC₅₀ values, generally range from about 0.2namomolar to about 10 micromolar.

We claim:
 1. A method for the treatment of certain disorders, whichcomprises administering to a subject in need of such treatment aneffective amount of a compound of the formula ##STR27## or apharmaceutically acceptable acid addition salt thereof, wherein B is NR₁R₂, CR₁ R₂ R₁₁, C(═CR₂ R₁₂)R₁, NHCR₁ R₂ R₁₁, OCR₁ R₂ R₁₁, SCR₁ R₂ R₁₁,NHNR₁ R₂, CR₂ R₁₁ NHR₁, CR₂ R₁₁ OR₁, CR₂ R₁₁ SR₁, or C(O)R₂ ;R₁ ishydrogen, or C₁ -C₆ alkyl which may be substituted by one or twosubstituents R₇ independently selected from the group consisting ofhydroxy, fluoro, chloro, bromo, iodo, C₁ -C₈ alkoxy, ##STR28## (C₁ -C₂alkyl), amino, NH(C₁ -C₄ alkyl), N(C₁ -C₄ alkyl) (C₁ -C₄ alkyl), S(C₁-C₆ alkyl), ##STR29## (C₁ -C₂ alkyl), SH, CN, NO₂, SO(C₁ -C₄ alkyl), SO₂(C₁ -C₄ alkyl), SO₂ NH(C₁ -C₄ alkyl), SO₂ N(C₁ -.sub. alkyl) (C₁ -C₂alkyl), and said C₁ -C₆ alkyl may contain one or two double or triplebonds; R₂ is C₁ -C₁₂ alkyl, aryl or (C₁ -C₁₀ alkylene)aryl wherein saidaryl is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,isothiazolyl, benzisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl,benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl,oxazolyl, or benzoxazolyl; 3- to 8-membered cycloalkyl or (C₁ -C₆alkylene) cycloalkyl, wherein said cycloalkyl may contain one or two ofO, S or N--Z wherein Z is hydrogen, C₁ -C₄ alkyl, benzyl or C₁ -C₄alkanoyl, wherein R₂ may be substituted independently by from one tothree of chloro, fluoro, or C₁ -C₄ alkyl, or one of hydroxy, bromo,iodo, C₁ -C₆ alkoxy, ##STR30## (C₁ -C₂ alkyl), S(C₁ -C₆ alkyl), NH₂,NH(C₁ -C₂ alkyl), N(C₁ -C₂ alkyl) (C₁ -C₄ alkyl), ##STR31## SH, CN, NO₂,SO (C₁ -C₄ alkyl), SO₂ (C₁ -C₄ alkyl), SO₂ NH(C₁ -C₄ alkyl), SO₂ N(C₁-C₄ alkyl) (C₁ -C₂ alkyl), and wherein said C₁ -C₁₂ alkyl or C₁ -C₁₀alkylene may contain one to three double or triple bonds; or NR₁ R₂ orCR₁ R₂ R₁₁, may form a saturated 3- to 8-membered ring of which the 5-to 8-membered ring may contain one or two double bonds or one or two ofO, S or N--Z wherein Z is hydrogen, C₁ -C₄ alkyl, benzyl or C₁ -C₄alkanoyl; R₃ is hydrogen, C₁ -C₆ alkyl, fluoro, chloro, bromo, iodo,hydroxy, amino, O(C₁ -C₆ alkyl), NH(C₁ -C₆ alkyl), N(C₁ -C₄ alkyl)(C₁-C₂ alkyl), SH, S(C₁ -C₄ alkyl), SO(C₁ -C₄ alkyl), or SO₂ (C₁ -C₄alkyl), wherein said C₁ -C₄ alkyl and C₁ -C₆ alkyl may contain onedouble or triple bond and may be substituted by from 1 to 3 substituentsR₈ independently selected from the group consisting of hydroxy, C₁ -C₃alkoxy, fluoro, chloro or C₁ -C₃ thioalkyl; R₄ is hydrogen, C₁ -C₆alkyl, fluoro, chloro, bromo, iodo, C₁ -C₆ alkoxy, amino, NH(C₁ -C₆alkyl), N(C₁ -C₆ alkyl) (C₁ -C₂ alkyl), SO_(n) (C₁ -C₆ alkyl), wherein nis 0, 1 or 2, cyano, hydroxy, carboxy, or amido, wherein said C₁ -C₆alkyls may be substituted by one hydroxy, trifluoromethyl, amino,carboxy, amido, ##STR32## NH(C₁ -C₄ alkyl), N(C₁ -C₄ alkyl) (C₁ -C₂alkyl), ##STR33## C₁ -C₃ alkoxy, C₁ -C₃ thioalkyl, fluoro, bromo,chloro, iodo, cyano or nitro; R₅ is phenyl, naphthyl, thienyl,benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl,furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl,thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl,pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, benzoxazolyl, oxazolyl,pyrrolidinyl, thiazolidinyl, morpholinyl, piperidinyl, piperazinyl,tetrazolyl, or 3- to 8-membered cycloalkyl or 9- to 12-memberedbicycloalkyl, optionally containing one or two of O, S or N--Z wherein Zis hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkanoyl, phenyl or phenylmethyl,wherein each one of the above groups may be substituted independently byfrom one to three of fluoro, chloro, bromo, formyl, C₁ -C₆ alkyl, C₁ -C₆alkoxy or trifluoromethyl, or one of hydroxy, iodo, cyano, nitro, amino,NH(C₁ -C₄ alkyl), N(C₁ -C₄) (C₁ -C₂ alkyl), COO(C₁ -C₄ alkyl), CO(C₁ -C₄alkyl), SO₂ NH(C₁ -C₄ alkyl), SO₂ N(C₁ -C₄ alkyl) (C₁ -C₂ alkyl), SO₂NH₂, NHSO₂ (C₁ -C₄ alkyl), S(C₁ -C₆ alkyl), SO₂ (C₁ -C₆ alkyl), whereinsaid C₁ -C₄ alkyl and C₁ -C₆ alkyl may be substituted by one or two offluoro, chloro, hydroxy, C₁ -C₄ alkoxy, amino, methylamino,dimethylamino or acetyl wherein said C₁ -C₄ alkyl and C₁ -C₆ alkyl maycontain one double or triple bond; with the proviso that R₅ is notunsubstituted phenyl; R₆ is hydrogen, C₁ -C₆ alkyl, fluoro, chloro,bromo, iodo, C₁ -C₆ alkoxy, formyl, amino, NH(C₁ -C₆ alkyl), N(C₁ -C₆alkyl)(C₁ -C₂ alkyl), SO_(n) (C₁ -C₆ alkyl), wherein n is 0, 1 or 2,cyano, carboxy, or amido, wherein said C₁ -C₆ alkyls may be substitutedby one hydroxy, trifluoromethyl, amino, carboxy, amido, ##STR34## NH(C₁-C₄ alkyl), N(C₁ -C₄ alkyl)(C₁ -C₂ alkyl), ##STR35## C₁ -C₃ alkoxy, C₁-C₃ thioalkyl, fluoro, bromo, chloro, iodo, cyano or nitro; R₁₁ ishydrogen, hydroxy, fluoro, chloro, COO(C₁ -C₂ alkyl), cyano, or CO(C₁-C₂ alkyl); and R₁₂ is hydrogen or C₁ -C₄ alkyl; with the proviso that(1) B is not straight chain C₁ -C₁₂ alkyl, (2) when R₅ is unsubstitutedcycloalkyl, R₃ and R₄ are hydrogen, and R₆ is hydrogen or methyl, then Bis not NHR₂ wherein R₂ is benzyl or thienylmethyl, and (3) when R₅ isp-bromophenyl, and R₃, R₄ and R₆ are methyl, then B not methylamino orhydroxyethylamino, said disorders being selected from the groupconsisting of panic, agoraphobia, social phobia, simple phobia,obsessive-compulsive disorder, post-traumatic stress disorder, singleepisode depression, recurrent depression, dysthymia, bipolar disorders,cyclothymia, postpartum depression, child abuse induced depression,sleep disorders, stress induced pain perception, fibromyalgia,fibromyalgic sleep disorders, rheumatoid arthritis, osteroarthritis,psoriasis, euthyroid sick syndrome, syndrome of inappropriateantidiarrhetic syndrome hormone (ADH), bulimia nervosa eating disorder,and obesity.
 2. A method according to claim 1 wherein said compoundisn-butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;di-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;ethyl-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;diethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;n-butyl-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;2-{N-n-butyl--N-[2,5-dimethyl-7-2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]-pyrimidin-4-yl]amino}-ethanol; 4-(1-ethyl-propyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;n-butyl-ethyl-[2,5-dimethyl-7-(2,4-dimethylphenyl)-7H-pyrrolo[2,3d]pyrimidin-4-yl]amine;2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidyl-4-yl]-(1-ethyl-propyl)amine;or2-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol.3. The method of claim 1 wherein R₁ is C₁ -C₆ alkyl which may besubstituted by one or two of substituents R₇ independently selected fromthe group consisting of hydroxy, fluoro, chloro, C₁ -C₂ alkoxy, andOCO(C₁ -C₂ alkyl).
 4. The method of claim 1 wherein R₃ is hydrogen,methyl, ethyl, chloro, or methoxy.
 5. The method of claim 1 wherein R₄and R₅ are independently selected from the group consisting of hydrogen,methyl or ethyl.
 6. The method of claim 1 wherein R₅ is phenylsubstituted by two or three substituents.
 7. The method of claim 1wherein R₅ is 2,4,6-trichlorophenyl,2,6-dichloro-4-trifluoromethylphenyl, 2,4,6-trimethylphenyl,2,4-dimethylphenyl, or 2,6-dimethylphenyl, 2-methyl-4-iodophenyl, or3,5-difluoromethylphenyl.